Phenothiazine drench compositions



' PHENOTHIAZINE DRENCH COMPOSITIONS Fred N. Brooks and Robert L. Rogers, Fort Worth, Tex.; 'Luna Alice Rogers, executrix of said Robert L. Rogers,

:deceased, assignors to Texas Phenothiazine Company,

Fort Worth, Tex., a corporation of Texas Application February 24, 1958 Serial No. 716,891

9 Claims. (Cl. 167-53) t No Drawing.

This invention is a continuation-in-part of our combined applications Serial No. 520,493 for Helminthous Infections Control Compositions, filed July 7, 1955, and Serial No. 520,494 for Helminthous and Tapeworm Infections "Control Compositions for Cattle, Sheep and Goats, filed Phenothiazine formulations of various types have been suggested and employed in many tests reported in veterinary literature and elsewhere. Some of these formulations have very desirable qualities such as appearance, function well in dosing syringes when freshly prepared,

atent 11 but they deteriorate upon standing in the container prior I to use and become too pasty and thick to use or they fail to function properly when introduced into the stomach such as the fourth stomach (abomasum) of ruminants. Even when freshly made, these formulations curdle when brought in contact with the digestive juices that contain minute to small percentages of acids, enzymes, sodium chloride, magnesium and calcium salts and other chemical compounds which are in solution, and act as electrolytes which alter the function of many wetting and suspending agents and medicaments. We found, for example, the bentonite suspensions of phenothiazine tend to thicken or congeal immediately upon contact with the digestive juices of the fourth stomach. This reaction with the normal and essential chemical elements, which elements are'necessary for proper digestive function, seems to interfere with the normal digestion and movement of the food and medicament as shown by our test projects. Sodium alginate, which is very useful in stabilizing suspensions has, for example, been found to curdle or congeal into a semi-solid mass or lamp, even worse than bentonite when vintroducedinto the abomasum and, even though a strong wetting agent such as sodium'heptadecyl sulfate was added to the suspension, it still curdled. It was reasonable to would tend to, prevent absorption by the host animal. Durin g tests on ruminants, employing well known phenojthiazine'formulations,-we found that excessive absorption was not prevented. In view of several undesirable" properties of bentonite and/or sodium alginate in phenothiazine suspensions, a search was 'made for additives ice able drench but, unexpectedly, upon adding more magnesium sulfate the suspension thinned to make a smooth free-flowing composition of a very desirable viscosity. To our surprise this suspension, resulting from the modification of the bentonite and/ or bentonite-sodium alginate ing for similar periods. Moreover, when our composition was tested in the same stomach fluids as mentioned above, we unexpectedly found that it remained free-flowing and easily dispersed. Another totally unexpected result of this new formulation was the comparatively high retention of the phenothiazine in the alimentary tract as shown by controlled animal tests in which the excretion of phenothiazine was determined.

It is well known that phenothiazine is not effective against the intestinal tapeworm (Moniezia) infecting sheep, goats and cattle. Therefore, the formula given hereinafter as Example A would not be expected to control this parasite. Numerous references in veterinary literature attest to the fact that the common intestinal tapeworm causes great economic loss as evidenced by depressed weight gain and a deterioration in the health of the animal. It is, therefore, within the scope of the invention to include a metallic arsenate in the improved formula. The inclusion of a metallic arsenate as an added ingredient of the preferred formula as given in Example A would not detract or take from the importance of the modification of the bentonite or the bentonitesodium alginate. Examples of formulas in which a metallic arsenate is employed are shown in Examples B, C and D.

This combination of additive materials also proved to be unexpectedly useful in lessening the tendency of treated animals to go off feed following treatment with the modified phenothiazine suspension even though the phenothiazine was of small particle size.-

The proportion of the magnesium sulfate to be incorporated in the drench composition will vary depending upon the conditions of use. Normally this will be between 4 and 30 percent by weight of the total drench composition. Preferably the proportions used are between 8 and i 25 percent by weight. t 'We discovered that the addition of sodium alginate to water-moistened lead arsenate tended to coat the particles of the latter. Investigating this further, we discovered that we were able to employ therapeutic doses containing an arsenate, in a phenothiazine-sodium alginate-arsenate drench, as a taeniacide, in a ratio of arsenate (lead I expect that such curdlin'g effect would prevent proper idispersion of the phenothiazine and that the curdling arsenate for example) to phenothiazine of 0.6:25, where- 55,.

phenothiazine, in an aqueous drench to function etfective- .ly as a taeniacide are 1:25 or greater than one part arseas the therapeutic conventional doses of lead arsenate to mate to twenty-five parts phenothiazine. Furthermore, it

is generally recognized that when metallic salts of arsenic .of hydrolyzation occurs which liberates various amounts 7 of arsenic into soluble forms of arsenic.

presence of the various elements contained in the bentoand undetermined arsenica'l compounds.

are added to water (aqueous solutions) a variable amount Now in the nite there is the possibility of the formation of'complex Even in the presence ofthe magnesium sulfate modified bentonite and "'watera certain amount of hydrolyzation of the arsenic "occurs but in much less quantities. One of the unexpected results of our discovery was that the addition of magnesium carbonate alleviated or. prevented the hydrolyza- -tion of arsenic and nullified the formation of soluble and fc omplex arsenic derivatives. When lead arsenate is employed in the presence of water and phenothiazine it is thought that certain hydrolyzation occurs and other undesirable changes probably occur in the lead arsenate. In effect it is possible that some part of the effectiveness of the lead arsenate is lost, and to provide a therapeutic dose, consequent increase in the arsenate content was necessary. Since the sodium alginate coats the arsenate, segregating the particles thereof, in a sense, from the other ingredients and preventing hydrolyzation and the formation of unknown and/or undesirable complex arsenical compounds, we have in fact accomplished a synergistic effect inasmuch as our invention is equally as effective We prefer Phenothiazine NF purified but may employ Phenothiazine NP and have used Phenothiazine having a mean particle diameter not exceeding microns. The lead arsenate is, preferably, standard acid lead arsenate.

The composition of Example A was employed in treating sheep No. 56, in comparison with treatment of sheep 62 with a conventional drench composition. These animals were confined in metabolism test pens. Excreta were recovered and moisture content of feces was determined, animals were similar in weight and breeding. Food rations, quantity and time of feeding were essentially the same. In the test, it was shown that the conventional, unmodified bentonite-sodium alg'inate-phenothia- Zine suspension caused an interference with normal digestive processes as judged by the lowered moisture content of the feces, and by the loss of appetite resulting in a weight loss of 7 pounds during the 3 day period post treatment that sheep 62 was on test. In contrast, sheep 56 receiving the formula set out in Example A, suffered no interference in normal digestive processes as shown by its retention of appetite, retention of normal moisture content in its feces resulting in no weight loss, in fact animal 56 gained a total of 8 pounds during the five day period following treatment. The results of the test were as follows:

Sheep No. Dosage and Formula Moisture content of feces Effects of Treatment 62 25 grams phenothiazine in Time of treatment-66.25%. Ate only food ration during first customary unmodified 23% hours post-treat- 24 hour period post treatment,

bentonite, sodium algiment-5l.25%. 42% hours slightly over ration during secnate suspension in water. post treatment-47.0%. end 24 period and consumed only 72 'hours post treatment-- of ration during third 24 hour 50.0%. period. Weight loss: 7 pounds during 72 hour test period. 25 grams phennthlazine, Normal moisture content Animal did not lose appetite dur- Example A.

magnesium sulphate in modified bentonitasodinm alginate suspension in water according to preferred formula given in of feces retained through ing test period, in fact it became test period.

more eager for food ration, eating its food quickly at each feeding period. Appeared normal throughout test. Weight loss: none, gained total of 8 pounds in a five day period post treatment.

Example A: Percent by weight Phenothiazine NF purified 28.57 Magnesium sulfate, U.S.P 23.81 Bentonite (Wyoming) 2.14- Sodium alginate 0.13 Water -u 45.35

Example B:

Phenothiazine NF purified 27.62 Magnesium sulfate, U.S.P. 22.83 Bentonite (Wyoming) 2.11 Sodium alginate 0.13 Lead arsenate 0.69 Magnesium carbonate, U.S.P. basic 0.20 Water 46.42

Example C:

Phenothiazine NF purified 35.73 Magnesium sulfate, U.S.P. 20.00 Bentonite (Wyoming) 1.87 Magnesium carbonate, U.S.P. basic 0.41 Lead arsenate 0.75 Sodium alginate 0.06 Water 41.18

Example D:

Phenothiazine NF purified 34.88 Magnesium sulfate, U.S.P 17.44 Bentonite (Wyoming) 1.83 Magnesium carbonate 0.81 Sodium arsenate 0.70 Sodium alginate 0.05 Water 44.29 100.00

The composition of Example B was tested in the treatment of calf No. 46 as compared with the treatment of calf 51 with a conventional drench formula. The two calves were grade Herefords and held in the same pen under dry-lot feeding conditions and were taking a full feeding of a conventional fattening ration when they were treated as follows on March 26, 1956:

Calf No. 51 was given a conventional drench formula containing phenothiazine and lead arsenate suspended in bentonite, sodium alginate and water. The phenothiazine dosage was at the level of 8 grams per lbs. of body weight and the lead arsenate dosage was 0.2 gram per 100 lbs. of body weight.

Calf No. 46 was given a drench made according to the composition disclosed herewith as Example B so that this animal received a dosage of henothiazine at the level of 8 grams per 100 lbs. of body weight and the lead arsenate dosage level was 0.2 gram per 100 lbs. of body weight.

The two calves were kept in thesame lot and on the same feed for seven weeks after treatment. By the end of this period calf No. 51 had shown an average daily gain of 2.43 lbs. Calf No. 46 had shown an average daily gain of 3.14 lbs. per day. Thus we found that the improved formula given to calf No. 46 gave a net return of 0.71 lb. per day above the conventional formula given to calf No. 51.

Referring to Example C, the drench was employed in treating sheep No. 62 while sheep 63 was treated as indicated below. These animals were confined in metabolism test pens for recovery of all excreta. Moisture determinations were made by drying fecal samples at 100 to C. for 24 hours and recording weight loss as percent" moisture.

This showsthat the formula of Example C 'caused less upset to the normal. digestive processesi The loss of appetite and loss of weight in animal 63 indicated the toxic effects of the unimproved formula. This difference in no weightloss in animal 62compared to a loss of 4.5 pounds in 'animal 63 is of economic importance.

6 arsenate made in the conventional manner with bentonite and water so that the phenothiazine dosage level was 10'grams per 100 lbs. body weight. His weight gain during the following 28 days was 28 lbs. which represented an average of 1.0 lb. per day. Thus we found that the improved composition herewith disclosed had Percent Moisture in feces Sheep No. Dosage and Formula Before 'lreat.- After 'lreat- Effect of Treatment ment ment Min. Max. Min. Max.

' 63..-. grams phenothiazine, 0.333 gram 58. 5 62.5 49. 0 56. 5 Ate 4 of food ration during first 24 hour "J f lend arsenatfln unmodified bento- 9.5 6.0 period. Ate 9g of food ration during nite suspensloniu water. second 24 hour period of test; post treatment. Weight loss, 4.5 pounds during 80 hour test period. 25 grams phenothiazine, 0.5 gram lead 49.0 51.75 50. 5 54. 75 'Ate all of food ration early in each 24 I 'arsenato, 14 grams magnesium sul- +1.5 +3.0 hour period post treatment. Ap-

xfate in modified hentonite-sodium neared normal clinically. Weight alginnte suspension with magneloss: none durmg 80 hour test period. slum carbonate as in Example 0.

I Employing the drench of Example D in treating sheep shown a net daily average gain of 0.36 lb. per day over .631 as compared with the treatment of sheep 62 with a 25 the conventional formula given to the same animal held ,conventional drench we ascertained thefollowing:

under similar conditions.

Percent Moisture in feces Sheep N Dosage and Formula Before Treat- After 'freat- Efl'ect of Treatment ment ment Min. Max. Min. Max

. 62; 25 grams phoonthiazlne, 0.5 gram 50- 63.0 67.0 55. 0 85- 0 A al Showed Signs of distress. develdium nrsr'nate in unmodified ben- -8.0 +18.0 oped diarrhea. Ate only food tonite suspension in'water. ration first 24 hour period posttreatment and ate ration during second 24 hour period. Weight loss: 6 pounds during 80 hour test period. 63 25 grams phenothiazine. 0.5 gram so- 51.0 59.75 53. 25 62. No signs of distress or diarrhea. Ate dium arsenate. l4 grams'magnesiurn +2.25 +2.25 food ration during first 24 hour sulphate. 'magncsium carbonate in p p e t t. an ly all mmlifi'cd buntonite'sodium, alginate of ration during the second 24 hour suspension in water as in Example D Weight 1085} 1 Pound dur-. D, ing 80 hour test period.

These animals(sheep 62 and 63) were confined in metabolism test pens for recovery of all excreta. Moisture'd'etetminations were made by drying fecal samples at 100to 105 C. for 24 hours and recording weight loss as percentmoisture. It is shown in this test that the unmodified formula given to animal 62 caused a. .:loss of moisture in the feces immediately after treatment followed by an excess of moisture content resulting in ".diarrhea, loss of appetite, signs of distress and culminating in a loss of- 6 pounds in weight during the test period. In contrast animal 63, receiving the preferred formula, showed only slight inappetence and lost only 1 pound in weight during the same test period. Animal 63 did not develop signs of distress nor develop diarrhea. In this test there is an indicated difference of 5 pounds in weight between the two animals.

A further test was set up so that two or more different formulations could be given to the same calf. (No. 78, a Hereford steercalf) in order to eliminate variations in individual animals (as suggested by a Texas A. & M. nutritionist). During and between each test pe riod the No 78 Hereford steer calf was kept in the same shaded pen with the same feeding and care. On August 1, 1956, he was given a drench containing phenothiazine and lead arsen'ate formulated in accordance with the composition of this invention as disclosed in Example B so that the phenothiazine dosage level was 10 grams per 100 lbs. body weight. This weight gain during the following 28 days was 38 lbs. which represented an average of l.36 lbs. per day. On November 5, 1956, he was given a drench containing phenothiazine and lead given three different formulations of phenothiazine. Dur- In addition a purebred Hereford steer calf No. 80 was ing and between tests he was given a daily ration consisting of a limited amount of 20% protein-grain pellets and U alfalfa hay plus prairie hay free choice. Following each (1) On July 24, 1956, calf No. was given a drench made according to Example B so that the dosage represented 10 grams of phenothiazine per lbs. body weight plus the normal lead arsenate dosage. His daily average weight gain for the following two weeks was 2.2 lbs. per day.

(2') On August 13, 1956, calf No. 80 was given a drench made according to a conventional formula using bentonite in water as the suspending medium. vThe dosage level was 10 grams per 100 lbs. body weight with the normal dosage of lead arsenate. His daily average weight gain during the following two weeks was 1.36 lbs. per day.

(3) On November 5, 1956, calf No. 80 was given a phenothiazine molasses composition mixed in his regular feed so that the phenothiazine dosage level was 10 grams per 100 lbs. body weight. His daily average weight gain during the following two weeks was 0.93 lbs. per day. I

In all three tests the phenothiazine had an average particle size of 9 to 11 microns as specified by the manufacturers from whom we obtained the material. In these tests involving the same individual animal, the results of 5..13522,918,403 7 t it entag'es Off ingredients C d 513; However:

ikew

the; pence age-of:meta'l1ic arse'nate nip yedthon's nfie'c tion eontroi; composition; 02: 25

: the: frr rm; of :a: reariyto u s e dre'nch 'cairtgonate; a; minor repetition of hentoniteg-a nrinor pro az eJheritdnite andn naigne siunisni p re: hein g in weight; in mpeniem re: the:

stifiici'ent tri:

of a suspension 'en'm henethiazine amin j f min 1*- proportionbisiodiumialg1i1ate,= pr o p'rt i f f suifaitezsufiieie'nt:tio niiodif' the bentonite endg stahil I the flow; characteristics of i th spnsion; and were; said pze oniensbeing byweigh 5A ieomposition re: vete rina'ry the form an :a- 1? 5 heep endi goats which comprise introducing into thiazine having a mean particle diameter not exceeding 7 claim 4. 30 microns, a minor proportion of bentonite from, 1.0.to 4.0 percent, a proportion of magnesium sulfate from 8.0 p to 30.0 percent, and water, said proportions being by 45 weight. i i

4. A composition for veterinary use in the form of. a water suspension comprising substantially 28.57 percent phenothiazine having an average particle size not exceedii1g 30 microns in diameter, 2.14 percent bentonite, 0.13.. 50 percent sodium alginate, 23.81 percent magnesium sulfate, and 45.35 percent water, said percentages being by weight. 1 I

5 A prepared ready-to-use drench. composition for References Cited in the file of this patent UNITED STATES PATENTS 2,407,486 Flenner Sept. 10,1946 2,439,532 Whiting Apr. 13, 1948 OTHER REFERENCES Hat-wood: Proc. of Wash. Helminthological 800., January 1953, pp. 29-31.

Milks: Veterinary Pharmacology, Materia Medica and Then, 6th ed., 1949, pp. 249, 300and 455. w

at'ersuspeneion comprising a rriajc i' plfoportion of hene-: i thei "alimentary: tract of animal Ethe composition of:

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 2,918,4 3

) December 22, 1959 Fred N, Brooks et a1,

Column 1, line 53, for "lamp" read lump 5 column 5, line .72, for "This" reed His column '7, line 6, f difference or "different" read Signed and sealed this 24th day of May 1960,

SEALI ttest:

KARL H. AXLINE ROBERT C. WATSON Attesting Oflicer Commissioner of Patents UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent NOa 279182403 December 22, 1959 Fred No Brooks et .al0

Column 1, line 53, for "lamp" read lump --5 column 5, line 72, for

"This" reed His column 7, line 6, for "different" read @a difference Signed and sealed this 24th day of May 1960 (SEAL) zittest:

KARL Ha AXZINE. ROBERT C. WATSON Attesting Officer Commissioner of Patents 

1. A HELMITHOUS INFECTION CONTROL COMPOSITION FOR VETERINARIAN USE, IN THE FORM OF A READY-TO-USE DRENCH, CONTAINING, AS ITS ESSENTIAL ACTIVE INGREDIETNS, PHENOTHIAZINE, BENTOINE AND MAGNESIUM SULFATE, SAID MAGNESIUM SULFATE BEING IN WEIGHT, IN PROPORTION TO THE WEIGHTS OF THE OTHER INGREDIENTS, SUFFICIENT TO RENDER THE BENTONITE FREELY FLOWABLE AND READILY DISPERSIBLE IN THE FLUIDS IN THE ANIMAL STOMACHS INTO WHICH SAID COMPOSITION IS INTRODUCED. 